PRENATAL ORIGINS AND POSTNATAL PERSISTENCE: DEVELOPMENTAL SHIFTS IN AUTISM SPECTRUM DISORDER GENE REGULATION

Thousands of common and rare genetic variants contribute to brain disorders, including autism spectrum disorder (ASD). However, the precise developmental windows and cell types in which these variants act remain poorly defined.

We integrated genetic, epigenetic, and transcriptomic data to identify how common and rare variants shape gene expression across prenatal and postnatal development in the human dorsolateral prefrontal cortex (dlPFC). We investigated temporal shifts in expression and chromatin accessibility across cell types and examined colocalization between ASD GWAS variants and cell type- and development-specific quantitative trait loci (QTLs).

We profiled 263 postmortem human dlPFC samples spanning 6 postconceptual weeks to 92 years using whole-genome sequencing, bulk RNA-seq, and single-nucleus 10x multiome sequencing (joint RNA-seq + ATAC-seq; n = 1,818,009 nuclei). We identified chromatin accessibility (caQTLs), expression (eQTLs), and splicing (sQTLs) quantitative trait loci. ASD and brain disorder GWAS datasets were analyzed using colocalization and trajectory analyses to determine temporal and cell-type-specific mechanisms.

We identified developmental transitions in regulatory architecture across neurons, distinguishing prenatal from postnatal mechanisms of ASD etiology. Many ASD-associated genes and variants colocalized with regulatory elements showing prenatal-specific activity, particularly in excitatory neurons. For example, XRN2 demonstrated prenatal colocalization with ASD GWAS but was absent postnatally. In contrast, genes involved in synaptic signaling and neuronal communication (e.g., SCN2A, SYNGAP1) exhibited postnatal upregulation.

Our cell type- and developmentally-resolved map reveals that ASD genes exhibit distinct temporal waves of gene regulation: genes expressed early prenatally may disrupt cortical neurodevelopment, while genes expressed postnatally impact neuronal communication and synaptic function.